Novel 6{62 -amino-steroids and production thereof

ABSTRACT

Novel 6 Beta -amino-steroids of the formula:   WHEREIN R1 is a hydrogen atom or an acyl group, R2 is a hydrogen atom or an aliphatic hydrocarbon group, R3 and R4 are each a hydrogen atom or an alkyl group, or, taken together with the adjacent nitrogen atom and with or without another hetero atom, form a nitrogen containing heterocyclic ring, and salts thereof, useful as hypocholesterolemic agents, hypolipidemic agents, antitumor agents or antiviral agents.

United States Patent [191 Mukawa 1 Oct. 14, 1975 [54] NOVEL GBPAMINO-STEROIDS AND PRODUCTION THEREOF [75] Inventor:

[73] Assignee: Shionogi & Co., Ltd., Osaka, Japan [22] Filed: Nov. 30, 1973 [21] Appl. No.: 420,460

Fumikazu Mukawa, Mino, Japan [30] Foreign Application Priority Data Dec. 6, 1972 Japan 47-12265 [52] US. Cl 260/239.5; 260/239; 260/55 R;

260/397.2; 260/397.5; 424/241 [51] Int. Cl. C07J /00 [58] Field of Search 260/239.5

[56] References Cited UNITED STATES PATENTS 3,123,623 3/I964 Sasaki 260/397.3

FOREIGN PATENTS OR APPLICATIONS 1,042,292 10/1966 United Kingdom 260/397.4

Primary ExaminerElbert L. Roberts Altorney, Agent, or Firm-Wenderoth, Lind & Ponack [57] ABSTRACT Novel 6B-amino-steroids of the formula:

6-Claims, No Drawings .NOVEL 6B-AMINO-STEROIDS AND PRODUCTION THEREOF This invention relates to novel 6fi-amino-steroids and salts thereof useful as hypocholesterolemic agents, hypolipidemic agents, anti-tumor agents or antiviral agents, and to a process for the preparation thereof. More particularly, the present invention is concerned with novel 6B-amino-steroids (I) of the formula:

' wherein R is a hydrogen atom or an acyl group, R is va hydrogen atom or an aliphatic hydrocarbon group, R and R are each a hydrogen atom or an alkyl group, or,

taken together with the adjacent nitrogen atom and v wherein R 'is a hydrogen'atom or an acyl group and R is a hydrogen atom or an aliphatic hydrocarbon group,

. with an amine (III) of the formula:

R HN a (in) '.wherein R and R are each a hydrogen atom or an alkyl group, or, taken together with the adjacent nitrogen atom and with or without another hetero atom,

forma nitrogen containing heterocyclic ring.

In the formulae, R, stands for a hydrogen atom or an acyl group such as an alkanoyl group (e.g. formyl, acetyl, propionyli), aralkanoyl group (e.g. phenylacetyl,

phenylpropionyl) or aryloyl group. (e.g. benzoyl, toluoyl, phthaloyl). The substituent represented by OR may be of aor B-configuration. R is a hydrogen atom or an aliphatic hydrocarbon group such as an alkyl or alkenyl group, having preferably up to carbon atoms. Preferred hydrocarbon groups are methyl,

ethyl, and the hydrocarbon substituents at position 1 7 of cholesterol, B-sitosterol or stigmasterol. When R and R represent an alkyl group, as examples of the said 'alkyl group may be mentioned alkyl groups having up to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, or adamantyl. R and R, may alternatively form a nitrogen-containing heterocyclic ring such as piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine, or Nalkylpiperazine, when taken together with the adjacent nitrogen atom and with or without another hetero atom.

The present process in accordance with the invention can be performed by the reaction between a 501,601- epoxy-steroid (II) and an amine (Ill) in the presence or absence of a solvent. The reaction proceeds generally under heating at a temperature of from 50C to 300C, preferably at C to 200C. The reaction is usually carried out in a polar solvent having a relatively high boiling point. Examples of such a solvent are ethylene glycol, propylene glycol, dimethylformamide, dimethylsulfoxide, alcohols with a high boiling point (e.g butyl alcohol, tertiary alcohol, amyl alcohol) and water. However, the reaction of the invention may proceed without such solvents, and an amount of amine (III) in excess of that undergoing reaction may serve as the reaction solvent. The present reaction is complete within a few to several-tens of hours, depending on the start-,

ing materials, solvent, and reaction temperature used. If necessary, the reaction may be carried out under an atmosphere of inert gas such as nitrogen or helium. After completion of the reaction, the desired 63- amino-steroids (I) may be separated and purified by solvent extraction, evaporation under reduced pressure, recrystallization, chromatography, or other conventional method, or a combined method thereof.

The starting material, 5a,6a-epoxy-steroid (II), can be prepared by epoxidising a corresponding A -steroid with an organic peracid, according to the method described in I-Ielv. Chim. Acta 20, 244 (I937), Ann. Chem. 508, 215 (1934) or J. Chem. Soc. p. 738 (1936).

Examples of the other starting material, amine (III), are primary, secondary, and tertiary amines such as ammonia, alkylamines (e.g. methylamine, ethylamine, propylamine, isopropylamine, butylamine, tertbutylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, methylisopropylamine, or adamantylamine), and heterocyclic amines (e.g. piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, or N-alkylpiperazine in which the alkyl moiety contains up to 6 carbon atoms).

When R in 6B-amino-steroids (I) stands for a hydrogen atom and/or at least one of R and R is a hydrogen atom, the amino steroid (I) may be acylated, if desired. This acylation may be performed according to the usual method, and may usually be carried out in pyridine or a suitable basic solvent, although it may proceed in a neutral solvent. The acylation may be accelerated by the addition of a suitable inorganic or organic basic substance. Examples of the acylating agents available in this invention are various kinds of acylating agents employed in the art, such as acid anhydrides or acid halides of alkanoic acids (e.g. formic acid, acetic acid, propionic acid), aralkanoic acids (e.g. phenylacetic acid, phenylpropionic acid), or arylcarboxylic acids (e.g. benzoic acid, phthalic acid Depending on the reaction conditions, starting materials, and acylating agents used, the acylation takes place at the hydroxy group of position 3 and/or at the amino group of position 6!? in the steroid nucleus. The acylated product can be separated and isolated in a conventional manner involving recrystallization, fractional precipitation, chromatography, or other suitable method. In general, when the acylation with aceticanhydride is effected under mild conditions in pyridine at about room temperature, the hydroxy group at position 3 is predominantly acylated. Also, the amino-steroid (1) in which R is an acyl group may be optionally deacylated by a known method to give the corresponding 3-hydroxy compound (I, R =1-1) The 6B-amino-steroids (I) obtained by the process of the inventioncan be, after or without isolation, converted into inorganic or organic acid addition salts which are valuable for pharmaceutical purposes. Such suitable salts are the hydrochlorides, hydroiodides, sulfates, nitrates, phosphates, carbonates, formates, acetates, propionates, oxalates, succinates, tartarates, malates, citrates, benzoates, and salicylates. Also, the amino-steroids of the invention may be converted into the quaternary ammonium salts by the known method using an alkyl halide.

The 6/31 amino-steroids of the invention possess strong hypolipidemic and hypocholesterolemic activities and they cause marked decreases in plasma levels of cholesterol, phospholipid, and triglyceride, and in the cholesterol/phospholipid ratio. For example, the test results on 6B-isopropylamino-5a-cholestane-3B,5- diol ('A) and 6B-isopropylamino-stigmast-22-en-3B,5adiol (B) are summarized in the following table.

Notez'The numbers in parentheses of the plasma" column are percent decreases. The test results were obtained in the following manner: \Vistar male rats weighing 250-280 g were'fed a diet with or without 0.03% test compounds daily for two weeks. and the decreases of lipid levels in plasma and liver were studied by colorimetric determination.

As shown in the table, the 6B-amino-steroids of the invention cause marked decreases in the level of plasma cholesterol and lipids. Also, such steroids do not show any significant effect on liver weight, liver cholesterol and liver, Phospholipid. Clofibrate, a well known hypolipidemic agent, has undesirable effects on liver. Therefore, such property of the present 63- amino-steroids is valuable in view of 'clinical application.

Another advantage of the 6B-amino-steroids is that they do not inhibit normal cholesterol biosynthesis. Gas chromatographic analysis showed no accumlation of cholesterol biosynthesis intermediates such as desmos terol, which can usually. be detected in the metabolites of nitrogen-containing steroids, in rats which had been subcutaneously injected with fi-isopropylamino-Sacholestane-3B,5-diol at a dose of 1 mg/day/rat for 10 days.

The acute toxicity of 6B-amino-steroids was studied 7 using DS mice weighing 20-23 g. The drugs were administered by subcutaneous or oral route at various doses of the test compounds, and the mice were placed in a cage. The mortality was determined 72 hours after administration. The acute toxicities (LD value) of 6B- isopropylamino-Sa-cholestane-3B,5-diol and 6B- isopropylamino-stigmast-22-en-3B,5a-diol were both higher than 1000 mg/kg.

It should be noted that the test data described above are shown only with respect to specific example compounds. However, since the other'compounds of this invention, as well as those described above have similar characteristics and advantages as medicaments, the 6B- amino-steroids of the present invention are highly useful and advantageous in the treatment or prevention of hypercholesterolemia, hyperlipidemia, atheromatous conditions and atherosclerosis of human beings and domestic animals.

The present 6B-amino-steroids can be administered.

orally or parenterally in per se conventional dosage forms, e.g. tablets, granules, powders, injections, liquids, suspensions or emulsions,roptionally with suitable carriers, stabilizers, emulsifiers, preservatives, buffers, isotonizing agents and/or wetting agents, where a therapeutically active amount of active ingredient is present contained.

The effective dose can be easily determined by a physician on the basis of the data herein described. For example, a typical clinical dose range of the 6B-aminosteroids is approximately several hundred 'y to several grams, preferably 300 mg to 1000'mg, for a normal adult.

The following examples are given solely for the purpose of illustration'and are not to be construed as limitative of this invention, many variations of which are possible.

EXAMPLE 1 A suspension of 5a,6a-epoxy-cholesterol(6.5 g), triethylene glycol ml) and isopropylamine (26 ml) is heated under an atmosphere of nitrogen gas at C for hours. Thereaction solution is added to ice.- The product is dissolved in dry chloroform, then water then extracted with chloroform. .The chloroform chloroform saturated with hydrogen bromide is added extract is washed with water, dried Over anhydrous s thereto. The mixture is allowed to stand at room temdium Sulfate and evapora ed u e reduced P e to perature and then evaporated under reduced pressure. gi e a residue- The residue iS r ry lliz fr m etha- 5 The resultant residue is recrystallized from an aqueous no] to give 4.54 g of 6B-isopropylamino-5a-cholestaneethanol to give 6B-propylamino-5a-cholestane-3fi,5- 36,5-diol, m.p. 170-l7lC, [M -15.5 (c 0.5, chlodiol hydrobromide in quantitative yield, m.p. roform), IR (KBr): 3528 (OH), 3282 (OH), 3192 2l8220C (decomp.).

(NH) cm",NMR (CDCl 5:0.64 (l8-CH ),0.73 (l9 Anal. Calcd. for C30H57ON.HBT.H2OI C, 64.2; H, CH 0.88, 0.86 (26-CH 27-CH 0.92, 0.96, 0.98, 10 10.4; N, 2.4. Found: C, 64.4; H, 10.4; N, 2.5. 1.02 (-CH EXAMPLE 3 2\ HO HO 5 =i 5a,6a-Epoxy-stigmasterol (6.5 g) is dissolved in tri- NHCH ethylene glycol (220 ml), and isopropylamine (23 ml) 3 is added. The mixture is heated at l75l80C for 18 Ana1 C I d f -C H O N C H, 12.0; N hours. When the reaction is complete, the mixture is Found; C, 732; H, 2 N, 2 treated as in EXAMPLE 1 to give a residue. The resi- The product (50 mg) is dissolved i chl f Satw due is recrystallised from methylene chloride-n-hexane rated with dry hydrogenchloride and the solution is 9 f d fi-l P B evaporated under reduced pressure to give crystals. Red101, yleld g, -P- 178 i ]0' crystallization from methanol-ethyl acetate gives 63 chloroform)- isopropylamino-5q-cholestane-3B,5-diol hydrochloride in quantitative yield, m.p. l961 97C. 4 Anal- Calcdfor C32H57O2N3 C,

To .a solution of 6B-isopropylamino-5a-cholesane- 35 FOImdI C, 3B 5-dio1 (100 mg) in methylene chloride (2 ml-) is aded 20% acetic acid (10 ml), and the mixture is The product (50 mg) is dissolved in methylene chlostirred. After removal of the methylene chloridelayer, an aqueous saturated solution of sodium chloride is added to the aqueous layer to precipitate crystals, which are recrystallized from methanol-ether to give the corresponding acetate, m.p. 193l94C.

ring. The aqueous phase is separated, and to it is added, dropwise, a saturated aqueous sodium chloride solution. The resultant crystals are collected by filtration and recrystallized from methanol-ether to give 63- isopropylamino-stigmast-22-en-3B,5a-diol tartarate in EXAMPLE 2 quantitative yield, m.p. l94196C.

NH-( CH -CH EXAMPLE 4 in the same manner as in EXAMPLE 1, but using O using 5a,6 -epoxy-B-sitosterol (0.3 g), triethyl- 5a,6a-epoxy-cholesterol (0.3 g), triethylene glycol (5 ene glycol (6 ml), and isopropylamine (0.8 ml), the ml) and propylamine (5.0 ml), 0.145 g of 63- same reaction as described in EXAMPLE 1 gives 63- propylamino-Sa-cholestane-3B,5-diol is obtained, m.p. isopropylamino-stigmastane-3B,5a-diol, m.p. l49-l52C, [011 14.1(c 0.3, chloroform). 156l57C, [a],, l2.l (c 0.5, chloroform).

ride (10 ml) then 10% tartaric acid is added with stir- 3 ,912,722 7 8 Anal. Calcd. for C l-I O N: C, 78.5 H,'12.1; N. 2.9. 6,8-lsopropylamino-stigmast-22-en-36,5a-diol (50 Found: C, 78.1; H, 12.0; N, 2.7. mg), obtained as in EXAMPLE 3, is acetylated in the same manner as in EXAMPLE 6 to produce 38- acetoxy-6B-isopropylaminostigmast-22-en-5a-ol, yield EXAMPLE 5 Triethylene glycol 5 ml) and piperidine 0.3 ml) are 34.8 mg, m.p. s1 s2c, a 25.6 (c 0.4, chloroadded to 5a,6a-epoxy-stigmasterol(0.3 g) and the mixform), IR (chloroform):33003500, 1735, 970 cm.

ture is heated at 165 -1 70C for 7 hours. After comple- Anal. Calcd. for C H' O N: C, 77.0; H, 1 1.2; N, 2.6. tion of the reaction, the mixture is poured into ice- Found: C, 76.9;H, 11.2; N, 2.5. water and then extracted with chloroform. The extract 7 EXAMPLE 8 v 4 C 11 1 1-1 ,GH H N CIL 3 H0 no NH-OH I is subjected to thin-layer chromatography on'silica gel 3 5,6a-Epoxy-5a-pregnan-33-01 (5.6 g) is added to triin' a solvent system of chloroform: ethyl acetateznethylene glycol (450 ml) containing isopropylamine hexane= 2:1:0.5 (v/v), thus yielding 0.11 g of 6B- ml) and the mixture is heated in an oil bath at Pi ri i igm -Z2- n-3B,5 0 m-p. about 190C for 18 hours. Working up the reaction 167l69 "C, 10 chloroform), 1R mixture in the same manner as in EXAMPLE 1, 3.4 g

(chloroform): 3350-3500 cm. I 'of 6B-isopropylamino-5a-pregnane-3B,5-diol is ob- Anal. Calcd. for C H O N: C, 79.4; H, 11.5; N, 2.7 tained, m.p. l95196C (recryst. from methanol),

F H. 4; N. a 33.3 (c 0.5, chloroform). I

EXAMPLE 6 Anal. Calcd. for C H O N: C, 76.3; H, 11.4; N, 3.7.

6B-Isopropylamino-5archo1estane-3B,5 diol (mg) Foundz'C, 76.5; H, 11.4; N, 3.71 obtained in EXAMPLE l 'is' added to a mixture of pyri- 50 The starting material, 5,6a-epoxy-5a-pregnan-3B-ol,

dine (1 ml) and acetic anhydride (0.5 ml) and the mixcan be prepared by the following procedure. To a soluture is allowed to stand at room temperature. The prodtion of 50z-pregnen-3B-0l (6.8 g) in methylene chloride uct obtained is recrystallized from ether to give 35.4 (150 ml) is added, dropwise, a solution of mmg of 3B-acetoxy-6B-isopr0pylamin0ch0leSta -561- chloroperbenzoic acid (4.5 g) in methylene'chloride P- 76O-77OC, l :lD 045, chloroform), IR ml) with stirring at 0C. After 3 hours, the reac- (chlorofofmfi 3300-3500, 1735 Cm-1- tion solution is treated in a conventional manner and Analcalcd for az sv a C, 76.2; H, 1 N, the residue is crystallized from methanol, thus yielding FOImdI 76.1; 11.1; N, 5,6a-epoxy-5a-pregnan-33-01, yield 5.7 g, m.p.

EXAMPLE 7 147-14sc, o 59.0 (c 0.49, chloroform).

EXAMPLE 9 a,6a-Epoxy-cholestan-3B-ol (0.5 g) is added to tri- NH-CH 5,oa-E poxy-5a-androstan-3B-ol (4.0 g) prepared by ethylene glycol ml) and then tert.-butylamine (8 the method described in Ber. 75, 597 (1942) is heated in triethylene glycol (200 ml) together with isopropylamine (4.0 ml) at 17S-180.C for 10 hours. The reaction mixture is then poured into ice-water and exml) is added. The mixture is heated in an oil bath at about 180185C for 20 hours. Work-up in the same manner as in EXAMPLE 1 gives 0.28 g of 6B-tert.- butylamino-5a-cholestane-3B,5-diol, m.p. 166167C tracted with chloroform. After removal of the solvent, 15 y m ethanol), l ln Chlorothe residue is recrystallized from methylene'chloridenhexane to give 6B-isopropylamino-Sa-androstane- 3B,5-di0l, yield 1.94] g, [a] '47..9 (c 0.4, chloroform).

Anal. Calcd. for C H O N2 C, 75.6; H, 11.2; N, 4.0. Found: C, 75.7; H, 11.2; N, 4.1.

EXAMPLE l0 5a,6oz-Epoxy-cholestan-3fi ol (200 mg) is heated together with adamantanamine 150mg) and water (1.2 ml) in a sealed tube at l-145C for 15 hours. The reaction solution is extracted with a mixed solvent of form).

Anal. Calcd. for C H O N: C, 78.2; H, 12.0; N, 2.9. Found: C, 78.0; H, 11.9; N, 2.7.

5,6a-Epoxy-5-cholestan-3B-0l benzoate (0.5 g) is dissolved in triethylene glycol (5 ml) and to this solution is added isopropylamine (0.5 ml). The mixture is heated at 180C for about 18 hours. Work-up in the same manner as in EXAMPLE 1 gives 0.34 g of 3B- benzoyloxy-6B-isopropylamino-Sa-cholestan-S-ol,

m.p. 174176C (recryst. from methanol), [01],, -2.4 (c 0.47, chloroform), IR (chloroform):

methylene chloride-methanol. The organic extract is 33004500, 1780, 1610, 1590 cm".

EXAMPLE 1 1 Anal. Calcd. for c,,H .-,,0,N. c, 78.5; H, 10.5; N, 2.4. Found: C, 78.4; H, 10.3; N, 2.4.

The product obtained above can also be prepared in a manner similar to that described in EXAMPLE 6, by treating 6B-isopropylamino-5a-cholestane-3B,5-diol with benzoyl chloride, in place of the acetic anhydride used in EXAMPLE 6.

11 EXAMPLE FOR REFERENCE H 3 /CH 110 NIHH 3 l \cn I -6/3-Isopropylamino-stigmast 22-en 3B,5a-diol (0.2 g) isadded to a mixture'of'ether and acetic acid'( 1:3 (v/v), ml). After addition of platin'ic oxide (50 mg), the mixture is shaken in a hydrogen stream at normal pressure. After three hours, the catalyst is filtered off and thefiltrate is adjustedto weakly alkaline pH with a dilute sodium carbonate solution. The alkaline solution is extracted with methylene chloride. The organic extract is treated in a conventional manner, to yield 613- 3B-benzoyloxy-6/3-isopropylamino-Sa-cholestan-S ol. 2. A 6B-Amino-steroid selected from the group consisting of compounds of the formula wherein R is a-member selected from the group consisting of hydrogen, alkanoyl of l-3 carbon atoms, aralkanoyl of 8-9 carbon atoms and aryloyl of 7-8 carbon atoms,

R is a member selected from the group consisting of hydrogen, alkyl of up to 10 carbon atoms and alkenyl of up to 10 carbon atoms, and 7 R and R are each a member selected from the group consisting of hydrogen and alkyl of up to 10 carbon atoms, or R and R together with the adjacent nitrogen atom, form a heterocyclic ring selected from the group consisting'of piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine and N-alkylpiperazines wherein the alkyl group contains up to'6 carbon atoms, and pharmaceutically acceptable salts thereof.

33A 6B-Amino-steroid selected from the group consisting of compounds of the formula R is a member selected from the group consisting of hydrogen, alkanoyl of l'3 carbon atoms, aralkanoyl of 8-9 carbon atoms, and aryloyl of 7-8 carbon atoms,

R is a member selected from the group consisting of hydrogen, alkyl or up to' 10 carbon atoms and alkenyl of up to 10 carbon atoms, and

R and R are each a member selected from the group consistingof hydrogen and alkyl of up to l 0 carbon atoms, or R and R together with the adjacent nitrogen atom, form a heterocyclic ring selected "fromthe group consisting of piperidine, pyrroli-.

' dine, piperazine, morpholine, thiomorpholine and N-alkylpiperazines wherein the alkyl group tains up to 6 carbon atoms, v and pharmaceutically acceptable salts thereof.

4. A 6B-Amino-st'eroid'selected from the group con-;

sisting of compounds of theformula I wherein R is a member selected from the group consisting of hydrogen, alkyl or up to '10 carbon atoms and alkenyl of up to 1-0 carbon atoms, and

R and R are each a member selected from the groupconsisting of hydrogen and alkyl of up to 10 carbon atoms, or R and R together with the adjacent nitrogen atom, form a heterocyclic ring selected con- 13 from the group consisting of piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine and N-alkylpiperazines wherein the alkyl group contains up to 6 carbon atoms, and pharmaceutically acceptable salts thereof.

5. A 6B-Amino-steroid selected from the group consisting of compounds of the formula 1,5-dimethyl-4- l,5-dimethylhexyl,'

14 consisting of piperidine, pyrrolidine, piperazine, morpholine, thiomorpholine and N-alkylpipera zines wherein the alkyl group contains up to 6 carbon atoms,

v 5 and pharmaceutically acceptable salts thereof.

6. A 6B-Amino-steroid selected from the group consisting of compounds of the formula wherein R is a member selected from the group consisting of hydrogen, ethyl, 1,5-dimethylhexyl, 1,5-dimethyl- 4-ethylhexyl and 1,5-dimethyl-4-ethyl-2-hexenyl,

and R and R are each a member selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyland adamantyl, or R and R together with the adjacent nitrogen atom, form a piperidine ring, and pharmaceutically acceptable salts thereof. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6B-PROPYLAMINO-5A-CHOLESTANE-3B,5-DIOL, 6B-ISOPROPYLAMINO-5A-CHOLESTANE-3B,K-DIOL, 6B-ISOPROPYLAMINO-STIGMAST-22-EN-3B,5-DIOL, 6B-ISOPROPYLAMINO-STIGMASTANE-3B,5A-DOL. 6B-PIPERIDINO-STIGMAST-22-EN-3B,5A-DIOL, 6B-ISOPROPYLAMINO-5A-PREGNAN-3B,5-DIOL 6B-ISOPROPYLAMINO-5A-ANDROSTANE-3B,5-DIOL, 6B-ADAMANTYLAMINO-5A-CHOLESTANE-3B,5-DIOL, 6B-TERT-BUTYLAMINO-5A-CHOLESTANE-3B,5-DIOL, 3B-ACETOXY-6B-ISOPROPYLAMINO-CHOLESTAN-5A-OL, 3B-ACETOXY-6B-ISOPROPYLAMINO-STIGMAST-22-EN-5A-OL, AND 3B-BENZOYLOXY-6B-ISOPROPYLAMINO-5A-CHOLESTAN-5-OL,
 2. A 6 Beta -Amino-steroid selected from the group consisting of compounds of the formula
 3. A 6 Beta -Amino-steroid selected from the group consisting of compounds of the formula
 4. A 6 Beta -Amino-steroid selected from the group consisting of compounds of the formula
 5. A 6 Beta -Amino-steroid selected from the group consisting of compounds of the formula
 6. A 6 Beta -Amino-steroid selected from the group consisting of compounds of the formula 